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ROS-Responsive Potassium Ionophore-Based Nanoplatform Potentiates Cancer Pyroptosis-Immunotherapy via ER Stress

ABSTRACT: Pyroptosis is an emerging programmed cell death with great potential in antitumor immunotherapy. However, the actual application of pyroptosis is hampered by its nonspecificity and inefficiency. In this study, a reactive oxygen species (ROS) responsive potassium (K+) ionophore-based nanoplatform rPPAA18C6 is constructed based on the triblock polymers PEG-PPBAEM-PAA18C6 to potentiate cancer pyroptosis and immunotherapy via the K+ metabolic disturbance mediated endoplasmic reticulum (ER) stress. The PEG (P) is used to prolong the circulation time in vivo, PPBAEM (r) is used to target the tumor cells and responds to the higher ROS, and PAA18C6 is used to perturb of K+ homeostasis. Moreover, rPPAA18C6 can also function as a drug carrier for chemodrug (doxorubicin, Dox). We find that rPPAA18C6@Dox provokes immune responses in melanoma (B16F10) via pyroptosis-related immunogenic cell death (ICD), in which damage-associated molecular patterns (DAMPs) are released to promote maturation of dendritic cells (DCs), activate cytotoxic T lymphocytes (CTLs), and convert immunosuppressive “cold” tumor to immunogenic “hot” tumor. Moreover, the combined therapy with anti-PD-L1 exhibits apparent tumor suppression far more than expected, suggesting a powerful candidate of rPPAA18C6@Dox for high-efficient immune checkpoint blockade (ICB) therapy. This study thus provides a promising strategy to specifically initiate pyroptosis and potentiate immunotherapy by perturbation of K+ metabolism via a smart nanoplatform.

ORGANISM(S): Mus musculus

PROVIDER: GSE256169 | GEO | 2025/01/01

REPOSITORIES: GEO

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Project description:A Cytotoxic T lymphocyte-inspired system capable of using ultralow-dose chemical drugs to manipulate cell death is needed to investigate the antitumour immunotherapy. Recent studies revealed pyroptosis, a proinflammatory type of cell death, could promote antitumour immune function. However, high-dose chemotherapy led to cytokine release syndrome by pyroptosis. Therefore, pyroptosis- inducing ultralow-dose chemotherapy was potential in preclinical and clinical research, but its efficacy, safety and the antitumour immune responses were not clear. Here, we established a near-infrared light controllable killing system (BIK system) by which ultralow-dose doxorubicin could be spatiotemporally transported to immunosuppressive tumour cells and mediate efficient pyroptosis. Compared with using DOX directly, the BIK system reduced total drug consumption to less than one- thirtieth the common dose in vitro. MPI imaging and fluorescence imaging showed our BIK system exhibited good tumour targeting and tumour penetration. We applied this system for pyroptosis-induced antitumor therapies, and the results showed that less than 43 µg kg-1 DOX was sufficient for GSDME-positive tumour regression with negligible injuries to major organs. Notably, the gasdermin-deficient 4T1 tumours could be controlled by combining BIK system with decitabine treatment. The antitumour immune function were proven to correlate with the impressive efficacy of pyroptosis-inducing ultralow-dose chemotherapy, and the concomitant immune memory prevented metastasis, but high-dose DOX led to poor T cells infiltration which caused immunosuppression and lung metastasis. Owing to the robust antitumour immune function induced by BIK system, advanced-stage bulky tumours could be controlled or shrunken by synergizing with anti-PD-1 therapy. This study provided new insights into the design of nanoassisted systems for activating the antitumour immune function by microstimulation; our application of the BIK system suggested that ultralow-dose chemotherapy was sufficient for inducing a robust pyroptosis-mediated antitumour immune function

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ROS-Responsive Potassium Ionophore-Based Nanoplatform Potentiates Cancer Pyroptosis-Immunotherapy via ER Stress

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